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Phosphate transport system II, previously shown to be responsible for high-affinity phosphate uptake under conditions of phosphorus starvation, is regulated by at least three genes: pcon-nuc-2, preg, and nuc-1. nuc-1 and nuc-2 mutants cannot be derepressed for phosphate transport system II, while pconc and pregc mutants are partially constitutive.
Murine thymus-derived lymphocytes can be sensitized in vitro to trinitrophenyl (TNP)-modified autologous spleen cells (1, 2). Cytotoxic effector cells were generated which were specific for TNP-modified target cells expressing the same H-2K and H-2D serological regions as the modified stimulator cells (3, 7). Spleen cells from two C57BL/10 congenic strains of mice sharing common I-C, S, and D regions, but differing at K, I-A, and I-B regions, generated different levels of lytic responses to the shared modified H-2Dd products upon sensitization with auto logous TNP-modified cells. Lymphocytes from an F1 between responder and nonresponder strain generated a level of cytolysis toward the H-2Dd modified specificity which was of the same order of magnitude as that obtained with the high responder, irrespective of whether F 1 or either parental strain of modified stimulator cell was used. These results suggest that the modification of H-2Dd products resulted in formation of new antigenic determinants in both parental strains. However, the difference observed in responsiveness appeared to be due to a gene or genes mapping in the K, I-A, or I-B region which influenced the ability of the responding lymphocytes to react to these modified H-2Dd products. Responsiveness was expressed as a dominant trait in the F1.
The tight regulation of meiotic recombination between homologs is disrupted in Brassica AAC allotriploids, a genomic configuration that may have facilitated the formation of rapeseed (Brassica napus L.) ∼7,500 years ago. Indeed, the presence of the haploid C genome induces supernumerary crossovers between homologous A chromosomes with dramatically reshaped distribution. However, the genetic mechanisms driving this phenomenon and their divergence between nascent and established lineages remain unclear. To address these concerns, we generated hybrids carrying additional C chromosomes derived either from an established lineage of the allotetraploid B. napus or from its diploid progenitor B. oleracea. We then assessed recombination variation across twelve populations by mapping male meiotic crossovers using single nucleotide polymorphism markers evenly distributed across the sequenced A genome. Our findings reveal that the C09 chromosome of B. oleracea is responsible for the formation of additional crossovers near pericentromeric regions. Interestingly, its counterpart from an established lineage of B. napus shows no significant effect on its own, despite having a similar content of meiotic genes. However, we showed that the B. napus C09 chromosome influences crossover formation through inter-chromosomal epistatic interactions with other specific C chromosomes. These results provide new insights into the genetic regulation of homologous recombination in Brassica and emphasize the role of genomic divergence since the formation of the allopolyploid B. napus.
BACKGROUND: Although endophytic microorganisms play a critical role in plant growth and stress resilience, the genetic basis underlying host selection of beneficial microbiota-particularly within the xylem-remains poorly understood. Cucumber (Cucumis sativus), as a crop model with a well-developed system for studying vascular biology, offers a valuable system to investigate the host genetic determinants of xylem microbiome assembly. RESULTS: By conducting population-level microbiome profiling across 109 cucumber accessions, we identified a conserved xylem microbiota dominated by Proteobacteria. Within this community, 20 core amplicon sequence variants (ASVs) were consistently present in xylem sap. Genome-wide association mapping identified a host genetic locus, CsXPR1, which encodes a tetratricopeptide repeat protein that regulates the abundance of the dominant xylem-colonized Pseudomonas ASV_4. Colonization patterns of ASV_4 varied across host genotypes and were correlated with CsXPR1 expression levels, suggesting a precision genetic regulation of bacterial entry into vascular tissues. Pseudomonas fulva strain 220, with 97% 16S rRNA gene identity with ASV_4, could colonize in cucumber xylem by inoculation of either roots or leaves. Genome analysis and plate assays revealed the biosynthesis of indole-3-acetic acid (IAA), solubilization of phosphate, and a range of plant beneficial traits in strain 220. Inoculation with strain 220 significantly enhanced growth in cucumber, but only in CsXPR1 haplotype that exhibited high gene expression and higher recruitment capacity of the strain. These benefits included notable increases in plant height (38%), stem diameter (36%), leaf area (61%), fresh and dry weight (51% and 85%, respectively), and a 4.57-fold increase in 4-methyleneglutamine content within the xylem sap. CONCLUSION: Our findings reveal a complete "gene-to-function" pathway where the host gene CsXPR1 mediates a genotype-dependent growth promotion. It achieves this by regulating the xylem colonization of a beneficial bacterium, Pseudomonas fulva, which in turn enhances plant growth by enriching the xylem sap with the key metabolite 4-methyleneglutamine. Video Abstract.
Normal phagocytic function is genetically determined but maintained in a rather narrow range of variation. Phagocytosis stimulation induced by different agents is variable according to species, strains or individuals. Variation is environmental, to a great extent, but has also a genetic component which differs in each case. Selective breeding for macrophage responsiveness to triolein stimulation was successful. However, the relevant genes have only a small effect on antibody synthesis. Macrophages of mice selected for high and low antibody synthesis have a similar phagocytic function but their capacities of antigen processing are quite different.
Laboratory strains of Drosophila melanogaster were screened for spatial variations in adult midgut alpha-amylase (1,4-alpha-D-glucan glucanohydrolase, EC 3.2.1.1) expression. No strain-specific differences were found anteriorly, but three patterns of activity were discerned in the posterior midgut: A, activity throughout most of the region; B, activity in the anterior part of the region; and C, little or no activity. Alleles of a control gene, map, are responsible for this tissue-specific regulation of activity; e.g., mapA homozygotes produce the A pattern and mapC homozygotes the C pattern. The map locus was placed at 2--80 +/- on the genetic map of chromosome 2R, about two crossover units distal to the Amy structural gene region for alpha-amylase. Electrophoretic studies showed that mapA is trans acting in mapA/mapC flies, allowing expression of amylase isozymes coded for by genes on the opposite chromosome. The map gene behaves as a temporal gene that is clearly separable from the tightly linked, duplicated Amy structural genes.
Merodiploid complementation analysis of the constitutive synthesis of the D-ribokinase and the D-ribose permease in Escherichia coli B/r has shown that the constitutive D-ribose operon is genetically controlled by a transdominant regulatory gene closely linked to the D-ribokinase and D-ribose permease structural genes. The regulatory mechanism for this operon shows no requirement for operator-repressor interaction, rather a truly positive control mechanism and thus suggests an extension of the operon model in its application to constitutive enzyme regulation in bacteria.
Data from genetic crosses of Peromyscus maniculatus and P. polionotus suggests that electrophoretic variants of liver alcohol dehydrogenase are coded by alleles at a single locus. These alleles, designated AdhF, AdhS, and AdhN, determine, respectively, the fast, slow, and not detectable (null) ADH electrophoretic phenotype. Heterozygotes (AdhF/AdhS) exhibit three bands on zymograms, suggesting a dimeric subunit structure for the enzyme. However, AdhF/AdhN and AdhS/AdhN animals exhibit a single band, suggesting that the AdhN allele does not produce a polypeptide subunit capable of dimerizing into an active molecule. Fast and slow electrophoretic phenotypes exhibit multiple bands which can be converted into single major fast and slow bands, respectively, upon treatment with oxidized or reduced NAD. Addition of NAD also stabilizes both the fast and slow enzyme to heat inactivation at 60 C for at least 30 min.
Inbred strains of mice excrete all three major urinary proteins (mups) when induced by testosterone, but differ as to the relative proportions and total levels of each mup present. We have now determined the urinary mup phenotypes before and after testosterone treatment of seven recombinant inbred strains derived from progenitor strains exhibiting different mup phenotypes. The results confirm previous observations indicating that total control of mup protein production is a multigenic process. One locus, Mup-a on chromosome 4, determines the relative mup protein proportions after induction by testosterone. Mup-a, together with other genetic sites, determines the basal mup proportions. Genes other than Mup-a determine the kinetics of mup induction and total mup excretion.
Three levels of variation are described in the response to sheep red blood cells (SRBC). Inbred strains of mice are distinguishable in terms of early or late kinetics of IgM response, high or low overall IgG response, and the relative expression of IgG1, IgG2a and IgG2b antibody in their response to SRBC. Results using C57BL/10 hybrid progeny strongly suggest a genetic control of these different aspects of the anti-SRBC response. The IgM kinetic pattern and the quantitative IgG response are regulated by two independent multigenic systems. Evidence is also presented for a distinction between the genes controlling the quantitative IgG response and those which control the 7 S isotypic pattern. IgG2a antibody expression seems regulated by a single gene. Neither group of genes involved in these various types of regulation seems directly linked to the H-2 complex or to the CH allotype. The hypothesis that 4 different sets of genes might control IgM, IgG1, IgG2a and IgG2b expression is discussed.
Bladder cancer is the ninth most common cancer worldwide, caused by genetic and environmental risk factors. Here, we report the findings of a multi-population meta-analysis of genome-wide association studies, including 32,470 individuals with and 1,753,462 without bladder cancer. We identify 70 independent risk loci, of which 43 are novel. Using a 70-marker polygenic risk score (HR = 1.63 per standard deviation), we increase the area under the curve from 0.71 (baseline risk model) to 0.75. Integrative analyses reveal the enrichment of the associated variants within accessible chromatin regions, and of the prioritized genes within pathways for xenobiotic metabolism and smoking behavior. Specifically, we show that the 15q25.1 variant rs71581744-ACCCC/A co-localizes with tissue-specific CHRNA3 expression, modulates mRNA stability, and associates with risk of muscle-invasive bladder cancer among current smokers. Together, these findings substantially expand the known genetic architecture of bladder cancer risk and highlight the germline regulation of smoking behavior as a mechanism driving bladder cancer susceptibility.
Induction of hepatic 4-methylumbelliferone UDP-glucuronosyltransferase (EC 2.4.1.17) by polycyclic aromatic compounds, such as 3-methylcholanthrene or beta-naphthoflavone, occurs in C57BL/6N, A/J, PL/J, C3HeB/FeJ, and BALB/cJ but not in DBA/2N, AU/SsJ, AKR/J, or RF/J inbred strains of mice. This pattern of five responsive and five nonresponsive mouse strains parallels that of the Ah locus, which controls the induction of aryl hydrocarbon (benzo[alpha]pyrene) hydroxylase (EC 1.14.14.2). Induction of the transferase is maximal in C57BL/6N mice with 200 mg of 3-methylcholanthrene/kg body weight; no induction occurs in nonresponsive DBA/2N mice even at a dose of 400 mg/kg. The rise of inducible transferase activity lags 1 or more days behind the rise of inducible hydroxylase activity and peaks 5 days after a single dose of 3-methylcholanthrene. In offspring from the appropriate backcrosses and intercross between C57BL/6N and DBA/2N parent strains, the genetic expression of 3-methylcholanthrene-inducible transferase activity is inherited as an additive (co-dominant) trait. This expression differs distinctly from that of the inducible hydroxylase activity, which is inherited almost exclusively as a single autosomal dominant trait in these same animals. The more potent inducer 2,3,7,8-tetrachlorodibenzo-p-dioxin induces the transferase more than 3-fold in C57BL/6N mice and less than 2-fold in DBA/2N mice, whereas the hydroxylase is induced equally (about 8-fold) in both strains. A dose of 3-methylcholanthrene given 3 days after 2,3,7,8-tetrachlorodibenzo-p-dioxin, at a time when hydroxylase induction in both strains is very high, does not enhance the rise in inducible transferase activity seen in C57BL/6N or DBA/2N mice which have received 2,3,7,8-tetrachlorodibenzo-p-dioxin alone. These data indicate that (a) the inducibility of two metabolically coordinated membrane-bound enzyme activities may be regulated by a single genetic locus, and (b) although the hydroxylase can be fully induced in the nonresponsive DBA/2N strain by 2,3,7,8-tetrachlorodibenzo-p-dioxin prior to 3-methylcholanthrene treatment, metabolites of the 3-methylcholanthrene treatment, metabolites of the 3-methylcholanthrene treatment, metabolites of the 3-methylcholanthrene, presumably present in the liver, are incapable of inducing further the transferase activity. The difference in sensitivity between 3-methylcholanthrene and the more potent inducer 2,3,7,8-tetrachlorodibenzo-p-dioxin for both the hydroxylase and the transferase activities suggests the possibility of a common receptor in regulating both enzyme induction processes.
In normal human fibroblasts, the synthesis of a cell surface receptor for plasma low density lipoprotein (LDL) is regulated by a sensitive system of feedback suppression. The number of functional LDL receptors declines by more than 20 fold when cellular stores of esterified cholesterol are increased by incubation of cells with an exogenous source of cholesterol. Fibroblasts from patients with the heterozygous form of familial hypercholesterolemia (FH) possess one functional allele and one nonfunctional allele at the LDL receptor locus. In the current studies, we have examined the effect that this deficiency produces upon the pattern of regulation of the single functional allele at the LDL receptor locus. Under growth conditions that induced a maximal rate of LDL receptor synthesis (that is, growth in the absence of an exogenous source of cholesterol), the FH heterozygote cells produced about one half as many functional LDL receptors as did the normal cells. More importantly, when grown in the presence of increasing amounts of exogenous cholesterol, the FH heterozygote and normal cells suppressed their respective LDL receptor activities in parallel. Over a wide range of LDL receptor activities, at each level of cellular esterified cholesterol, the FH heterozygote cells expressed about one half as many receptors as did the normal cells. These data indicate that in the FH heterozygote cells, the receptor regulatory mechanism dictates that the normal allele produce only the amount of gene product that it would normally produce at a given level of cellular esterified cholesterol. The failure of the regulatory mechanism to stimulate the normal allele at the LDL receptor locus to produce twice its normal amount of gene product leaves the FH heterozygote cells with a persistent 50% deficiency in LDL receptors under all conditions of cell growth.
BACKGROUND: Alternative polyadenylation (APA) is a key post-transcriptional mechanism that regulates gene expression by modulating 3'UTR length, its dysregulation has been implicated in carcinogenesis. How genetic variants influence APA to affect hepatocellular carcinoma (HCC) prognosis remains unclear. METHODS: Prognosis-APA quantitative trait loci (apaQTL) were performed using genotype and APA profiling from TCGA data. A two-stage survival analysis in 848 Chinese and 369 TCGA LIHC patients and functional validation were used to identify prognostic apaQTL in HCC progression. RESULTS: A total of 2,025 and 817 significant APA events were identified in Chinese and TCGA cohort, respectively. Besides, 859 events were associated with poor prognosis in HCC and enriched in RNA splicing / metabolism pathways. We detected 32,034 significant apaQTLs, predominantly enriched in 3'UTRs and RBP-binding regions. CPEB3 was prioritized as a key APA regulator RBP; its low expression correlated with poor patient survival and promoted proliferation, migration, and invasion in HCC cells. Notably, a functional apaQTL variant rs2037547, located in GSK3B and mediated by CPEB3, demonstrated a poor survival of HCC patients in both cohort (pooled HR=1.29, p=0.016). Mechanistically, rs2037547 promoted aberrant APA at proximal poly(A) sites of GSK3B through CPEB3, leading to increased expression of short 3'UTR isoform. This regulatory alteration enhanced HCC cell proliferation, invasion, and migration, and contributed to HCC progression. CONCLUSION: These findings elucidated the distinct role of apaQTL-mediated APA dysregulation in HCC prognosis, providing insights for prognostic stratification and potential targets for personalized therapy in HCC.
The effects of orthophosphate and mutations in the regulatory genes of alkaline phosphatase on the activities of pyrophosphatase and polyphosphatase of E. coli were studied. It was shown that orthophosphate represses the synthesis of alkaline phosphatase as well as that of polyphosphatase without having any effect on pyrophosphatase. The genes phoR and phoS are involved in the formation of a repressory complex both for alkaline phosphatase and polyphosphatase. The gene phoT is probably involved in a partial repression of pyrophosphatase synthesis.
People with HIV exhibit elevated inflammation and cardiovascular risk despite antiretroviral therapy. To define the genetic architecture of inflammasome-associated inflammation, we performed whole-genome sequencing and quantified plasma IL-6, IL-1β, and IL-18 in 1,000 ART-suppressed PWH from the U.S. Military HIV Natural History Study. Genome-wide analyses identified 14 loci implicating antiviral defense (DDX17, DDX41, EEA1, BCL11A), lipid metabolism (ABCA1, ABCA12, ABCC1, AGMO), and vascular remodeling (KLHL29, RNF213, ETV1). Transcriptome-wide analyses across cardiovascular and immune tissues identified regulatory programs linking interferon signaling, immune activation, and vascular biology to circulating cytokine levels. Mendelian randomization analyses supported causal relationships between inflammasome-associated cytokines and vascular events. Functional integration with genome-wide CRISPR perturbation datasets in primary CD4+ T cells linked cytokine-associated loci to HIV antiviral pathways and cytokine regulatory networks. External validation in cohorts without HIV demonstrated pathway-level convergence despite limited variant-level overlap. These findings define genetic mechanisms linking inflammasome signaling, antiviral defense, and cardiovascular risk.
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